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ObjectiveTo systematically review evidence regarding ataxia treatment.MethodsA comprehensive systematic review was performed according to American Academy of Neurology methodology.ConclusionsFor patients with episodic ataxia type 2, 4-aminopyridine 15 mg/d probably reduces ataxia attack frequency over 3 months (1 Class I study). For patients with ataxia of mixed etiology, riluzole probably improves ataxia signs at 8 weeks (1 Class I study). For patients with Friedreich ataxia or spinocerebellar ataxia (SCA), riluzole probably improves ataxia signs at 12 months (1 Class I study). For patients with SCA type 3, valproic acid 1,200 mg/d possibly improves ataxia at 12 weeks. For patients with spinocerebellar degeneration, thyrotropin-releasing hormone possibly improves some ataxia signs over 10 to 14 days (1 Class II study). For patients with SCA type 3 who are ambulatory, lithium probably does not improve signs of ataxia over 48 weeks (1 Class I study). For patients with Friedreich ataxia, deferiprone possibly worsens ataxia signs over 6 months (1 Class II study). Data are insufficient to support or refute the use of numerous agents. For nonpharmacologic options, in patients with degenerative ataxias, 4-week inpatient rehabilitation probably improves ataxia and function (1 Class I study); transcranial magnetic stimulation possibly improves cerebellar motor signs at 21 days (1 Class II study). For patients with multiple sclerosis–associated ataxia, the addition of pressure splints possibly has no additional benefit compared with neuromuscular rehabilitation alone (1 Class II study). Data are insufficient to support or refute use of stochastic whole-body vibration therapy (1 Class III study).

Objective: To assess the frequency of mutations in C19orf12 in the greater neurodegeneration with brain iron accumulation (NBIA) population and further characterize the associated phenotype. Methods: Samples from 161 individuals with idiopathic NBIA were screened, and C19orf12 mutations were identified in 23 subjects. Direct examinations were completed on 8 of these individuals, and medical records were reviewed on all 23. Histochemical and immunohistochemical studies were performed on brain tissue from one deceased subject. Results: A variety of mutations were detected in this cohort, in addition to the Eastern European founder mutation described previously. The characteristic clinical features of mitochondrial membrane protein-associated neurodegeneration (MPAN) across all age groups include cognitive decline progressing to dementia, prominent neuropsychiatric abnormalities, and a motor neuronopathy. A distinctive pattern of brain iron accumulation is universal. Neuropathologic studies revealed neuronal loss, widespread iron deposits, and eosinophilic spheroidal structures in the basal ganglia. Lewy neurites were present in the globus pallidus, and Lewy bodies and neurites were widespread in other areas of the corpus striatum and midbrain structures. Conclusions: MPAN is caused by mutations in C19orf12 leading to NBIA and prominent, widespread Lewy body pathology. The clinical phenotype is recognizable and distinctive, and joins pantothenate kinase–associated neurodegeneration and PLA2G6 -associated neurodegeneration as one of the major forms of NBIA.

Objective: We aimed to review the English and Chinese literature on Pa Ping and to confirm by personal interview the story of how its pathogenesis was uncovered. Background: In 1930, Dr. Alexander Stewart Allen noticed a pattern of illness arising in the region of Kiating, China. Area residents began presenting to local hospitals with nausea, vomiting, and diarrhea, and what emerged was a clinical picture of a gradual ascending paralysis that could result in death, termed Pa Ping. All 3 patients observed by Dr. Allen were male, had no family history of the disease, and had recently eaten before the onset of paralysis. Pa Ping developed in Dr. Allen himself, but he survived. Methods: Medical literature was reviewed for primary sources. Interviews of living descendants and friends of the doctors in China and North America were conducted and information was corroborated by written records. Results: Dr. Huang, with the National Central University College of Medicine, noticed a striking similarity between Pa Ping and familial periodic paralysis in 12 patients and reported 2 patients with Pa Ping treated with potassium citrate who experienced a reversal of the paralysis. Dr. K.T. Du analyzed meals of patients with Pa Ping seen by Dr. Zhe Tung and found barium in concentrations as high as 25.7%. This finding was confirmed by administering barium chloride to animals, which recapitulated the human syndrome. Conclusions: Although Dr. Huang had correctly noticed an underlying potassium depletion in patients with Pa Ping, the observations of Dr. Zhe Tung and Dr. K.T. Du ultimately established barium-induced hypokalemia as the underlying cause.

Objective: To examine the potential validity of performance measures and examination-based scales in Friedreich ataxia (FA) by examining their correlation with disease characteristics. Methods: The authors assessed the properties of a candidate clinical outcome measure, the Friedreich Ataxia Rating Scale (FARS), and simple performance measures (9-hole peg test, the timed 25-foot walk, PATA test, and low-contrast letter acuity) in 155 patients with FA from six institutions, and correlated the scores with disease duration, functional disability, activity of daily living scores, age, and shorter GAA repeat length to assess whether these measures capture the severity of neurologic dysfunction in FA. Results: Scores for the FARS and performance measures correlated significantly with functional disability, activities of daily living scores, and disease duration, showing that these measures meet essential criteria for construct validity for measuring the progressive nature of FA. In addition, the FARS and transformed performance measures scores were predicted by age and shorter GAA repeat length in linear regression models accounting for sex and testing site. Correlations between performance measures were moderate in magnitude, suggesting that each test captures separate yet related dimensions of neurologic function in FA and that a composite measure might better predict disease status. Composite measures created using cohort means and standard deviations predicted disease status better than or equal to single performance measures or examination-based measures. Conclusions: The Friedreich Ataxia Rating Scale, performance measures, and performance measure composites provide valid assessments of disease progression in Friedreich ataxia.

Background: Central core disease (CCD) and nemaline rod myopathy are generally considered two genetically and histologically distinct disorders. CCD is defined by the presence of well-demarcated round cores within most myofibers. Nemaline rod myopathy is distinguished by the presence of characteristic nemaline bodies within myofibers. The simultaneous occurrence of both cores and rods in the same muscle biopsy has been described, but no gene mutations have been reported yet for this condition. Objective: To describe a family containing 16 affected individuals in six generations with an autosomal dominant congenital myopathy that shows clinical and histologic features of both CCD and nemaline myopathy, and to determine the genetic etiology and protein composition of the cores/rods in this family. Methods and Results: The results of linkage analyses excluded involvement of the two autosomal dominant nemaline myopathy loci on chromosome 1, but were consistent with a localization of the disease gene at the CCD locus on chromosome 19q13.1 (ryanodine receptor). SSCP analysis and DNA sequencing identified a novel Thr4637Ala mutation in the transmembrane region of the ryanodine receptor protein. Immunofluorescence studies of patient muscle biopsies showed the central cores to stain for ryanodine receptor. Conclusions: These data suggest that the occurrence of nemaline bodies can be a secondary feature of CCD, and that genetic studies on previously reported core/rod families should be targeted to the ryanodine receptor locus. The results of the immunofluorescence studies suggest that the cores contain excess abnormal ryanodine receptor protein.

Earlier we have shown alterations in immunoreactivity (IR) to the calcium-binding proteins parvalbumin (PV) and calbindin D-28k (CaB) in surviving Purkinje cells of patients with spinocerebellar ataxia-1 (SCA-1). In the present study we determined PV and CaB expression (by immunohistochemical and immunoblot analyses) in Purkinje cells of transgenic mice (TM) expressing the human SCA-1 gene with an expanded (line B05) and normal (line A02) CAG tract, as well as in age-matched nontransgenic mice(nTM). Heterozygotes in the B05 line develop progressive ataxia beginning around 12 weeks of age. A02 animals are phenotypically indistinguishable from wild-type (nontransgenic) animals. In the cerebella of 8-, 9-, and 12-week-old TM-B05 there was a progressive decrease in PV IR in Purkinje cells compared with nTM and TM-A02. Parvalbumin immunostaining in interneurons was well preserved in all groups. A progressive decrease was also observed in CaB IR in Purkinje cells of 8-, 9-, and 12-week-old TM-B05. Cerebellar Purkinje cells of 6-week-old TM-B05, which exhibit no ataxia and even lack demonstrable Purkinje cell loss, also revealed reduction in PV IR. This change was matched by a significant decrease in the amount of cerebellar PV in 6-week-old TM-B05 as determined by Western blot analysis. Calbindin D-28K immunohistochemistry did not detect any marked changes in CaB IR within Purkinje cells at 4 weeks. However, at 6 weeks immunostaining and immunoblot analysis revealed a significant decrease in CaB in TM-B05 compared with controls. These data suggest that decreased levels of calcium-binding proteins in Purkinje cells in SCA-1 transgenic mice may cause alteration in Ca2+ homeostasis.

The distribution of two calcium-binding proteins, calbindin D28k (CaBP) and parvalbumin (PV), was investigated by immunohistochemistry in the brains of three individuals dying of nonneurologic illness and three patients with spinocerebellar ataxia-1 (SCA-1). SCA-1 has recently been proven to be due to an unstable CAG repeat mutation on chromosome 6. In the cerebellum of control individuals the Purkinje cells showed strong immunoreactivity to CaBP. Other cells were CaBP-negative. Parvalbumin was highly localized to Purkinje, basket, stellate, and Golgi cells. All surviving Purkinje cells in SCA-1 were strongly immunoreactive to CaBP. The number of PV-immunoreactive Purkinje cells was markedly reduced in SCA-1. In addition, there was a significant decrease in the intensity of PV immunostaining within the individual Purkinje cells compared with controls. However, in the hippocampus, temporal cortex, and lateral geniculate scattered PV-positive neurons were seen in SCA-1 patients, similar to those in controls. The present results suggest that the decreased PV-immunoreactivity in the surviving Purkinje cells in SCA-1 may reflect biochemical alterations preceding Purkinje cell degeneration.NEUROLOGY 1996;47: 249-253

The authors report six patients with tick paralysis seen over 5 years. Clinical and electrodiagnostic findings failed to adequately distinguish tick paralysis from Guillain-Barré syndrome in these patients. Finding a tick attached to the scalp or the nape of the neck and removing it resulted in rapid clinical improvement.

We congratulate Sorenson et al.1 for their well-executed IGF-1 trial in patients with amyotrophic lateral sclerosis (ALS). While the title appropriately reflects the subcutaneous mode of IGF-1 delivery, the article fails to distinguish this critical limitation. What is the bioavailability in CSF and brain parenchyma in humans treated twice daily with 0.05 mg/kg IGF-1? Animal studies indicate that subcutaneous delivery of ∼0.8 mg/kg IGF-1 results in a maximal CSF concentration of 3 ng/mL IGF-1 at 2 hours postinjection.2 This equates to 0.4 nM IGF-1 in CSF at peak. The Sorenson et al. trial dose was 16-fold lower, suggesting that the maximal CSF concentration in patients would be 0.025 nM. The Kd of the IGF-1 receptor is 0.15 nM.3 Therefore, at 0.025 nM, only 14% of high-affinity and less than 1% of low-affinity receptors will be occupied. Likewise, the concentration of IGF-1 in CSF overestimates the bioavailable concentration within the brain parenchyma. IGF-1 injected into the lateral ventricle of rats exhibits a half-life of only 12 minutes in the CSF and penetrates …

Measuring the severity of neurologic dysfunction in patients with inherited ataxias, including Friedreich ataxia (FA), is difficult because of the variable rate of progression, the variable age at onset and the variety of neural systems that may be affected. The authors discuss the problems related to rating scales in the ataxias, report a neurologic rating scale for FA, and demonstrate acceptable interrater reliability of the instrument.

Objective: To investigate the molecular basis of autosomal dominant limb-girdle muscular dystrophy (AD-LGMD) in three large new families. Methods andResults: Genome-wide linkage was performed to show that the causative gene in all three families localized to chromosome 21q22.3 (Zmax = 10.3; θ = 0). This region contained the collagen VI α1 and α2 genes, which have been previously shown to harbor mutations causing a relatively mild congenital myopathy with contractures (Bethlem myopathy). Screening of the collagen VI α1 and α2 genes revealed novel, causative mutations in each family (COL6A1—K121R, G341D; COL6A2—D620N); two of these mutations were in novel regions of the proteins not previously associated with disease. Collagen VI is a ubiquitously expressed component of connective tissue; however, both limb-girdle muscular dystrophy and Bethlem myopathy patients show symptoms restricted to skeletal muscle. To address the muscle-specific symptoms resulting from collagen VI mutations, the authors studied three patient muscle biopsies at the molecular level (protein expression). A marked reduction of laminin β1 protein in the myofiber basal lamina in all biopsies was found, although this protein was expressed normally in the neighboring capillary basal laminae. Conclusions: The authors’ studies widen the clinical spectrum of Bethlem myopathy and suggest collagen VI etiology should be investigated in dominant limb-girdle muscular dystrophy. The authors hypothesize that collagen VI mutations lead to muscle-specific defects of the basal lamina, and may explain the muscle-specific symptoms of Bethlem and limb-girdle muscular dystrophy patients with collagen VI mutations.

Fragile X syndrome (FXS) is a common cause of inherited mental retardation in boys. (More information about FXS can be found on the next page.) It is caused by a defect in a gene located on the X chromosome that is inherited from the mother. The gene in the mother carries a “premutation” which, when passed on to her son, expands to a “full” mutation that produces the signs of fragile X syndrome. The mother who carries the “premutation” does not have mental retardation because she also carries a normal X chromosome. She may have inherited the premutation from her father. This grandfather does not have mental retardation either because the gene only carries a “premutation.” However, some of these grandfathers develop a progressive tremor (shaking) and gait ataxia (unsteadiness) later in life, known as fragile X tremor-ataxia syndrome (FXTAS). Even more rarely, the mother with the premutation may develop FXTAS. This issue of Neurology has two papers that further describe FXTAS, as well as an editorial on the subject. One of the papers, by Hall et al.,1 is from the same group of researchers who originally reported this syndrome in 2001. In the clinics where the boys with FXS were treated, the mothers indicated that their fathers (the boys’ maternal grandfathers) were having neurologic problems. Sixty-two family members were found to have the fragile X premutation by genetic testing. “Definite” FXTAS was diagnosed if the patients had a tremor with movement (intention tremor) or ataxia when walking with either 1) a very typical abnormality on brain MRI scan or 2) the disease was confirmed on autopsy. Twenty of the 62 met this …

To the Editor: The editorial by Rosenberg [1] is a superb analysis of the current genotype situation in the field of the hereditary ataxias. Rosenberg is quite right in his comments that the genotype has great importance in clarifying the issue of correlation …

X-linked dystrophinopathy is the most common cause of isolated cases of myopathy in males. To investigate dystrophin abnormalities as a cause of myopathy in girls and women, we used dystrophin immunocytochemistry to study muscle biopsies from 505 girls and women with neuromuscular disease. Forty-six muscle biopsies showed a combination of fibers containing or lacking dystrophin; this mosaic immunostaining pattern denoted a carrier status. Twenty-one of 46 (45.6%) had a family history of Duchenne muscular dystrophy in males. Twenty-five of 46 (54.3%) were isolated cases, with no previous family history of neuromuscular disorder. The laboratory findings of the isolated cases were consistent with the familial cases; all showed myopathic histopathology and abnormal elevations of serum CK. The clinical presentations of the isolated cases varied but were consistent with the familial cases: 40% (10/25) of isolated cases showed proximal limb weakness before age 10, 24% (6/25) presented with myalgias or cramps, 24% (6/25) presented with incidental findings of grossly elevated CK levels, 8% (2/25) noted easy fatigue, and 4% (1/25) had slowly progressive proximal limb weakness beginning at age 45. From our data, the clinical criteria for consideration of an underlying dystrophinopathy in isolated female cases of myopathy are CK levels greater than 1,000 IU/l and myopathic histopathology. About 10% of the isolated cases of hyperCKemic myopathy (25/210) were proven by dystrophin analysis to have a dystrophinopathy as the cause of their disease (manifesting carriers of Duchenne dystrophy). However, we feel that this may be an underestimate. The correct diagnosis in these patients is imperative for appropriate genetic counseling to the patients and their families.

We studied a family with essential tremor of the arms. Some members also had tremor of the trunk and legs on standing, but not on walking, sitting, or reclining. Tremor was evoked, regardless of body or limb position, by strong tonic contraction of the appropriate muscles; it was a type of static postural tremor. Beta-adrenergic blockers had no effect on the tremor of the trunk or legs, but clonazepam was beneficial.

The effect of muscle immobility, with and without prior vigorous exercise, on amplitude and area of the compound muscle action potential (CMAP) to supramaximal nerve stimulation was studied in a family with hyperkalemic periodic paralysis. Amplitude and area of different CMAPs were measured during basal state, sustained immobility, and after brief maximal voluntary exercise of these muscles. Sustained immobility reduced the amplitude and area of the CMAP, with maximal effect occurring after 30 minutes. Though brief intense exercise seemed to minimally accentuate these effects of subsequent immobility at certain times, serial CMAP monitoring over 60 minutes did not reveal major differences between exercised and nonexercised muscles. Muscle immobility in itself can alter the CMAP in hyperkalemic periodic paralysis. Prior intense muscle exercise may accentuate this to some degree. This appears to be the electrophysiologic correlate of the characteristic symptom of focal weakness induced by rest after exercise.